Normal haemostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution. The complex interactions between blood cells, specific plasma proteins and the vascular surface maintain the fluidity of blood unless injury and blood loss occurs. Many significant disease states are related to abnormal haemostasis e.g. local thrombus formation due to rupture of atherosclerotic plaque is a major cause of acute myocardial infarction and unstable angina. Treatment of an occlusive coronary thrombus by either thrombolytic therapy or percutaneous angioplasty may be accompanied by acute thrombolytic reclosure of the affected vessel.
Thrombotic diseases remain one of the leading causes of death in developed countries despite the availability of anticoagulants such as warfarin, heparin and low molecular weight heparins, and antiplatelet agents such as aspirin and clopidogrel. The oral anticoagulant warfarin inhibits the post-translational maturation of coagulation factors VII, IX, and X and prothrombin and has proven effective in both venous and arterial thrombosis. However, warfarin's usage is limited because of its narrow therapeutic index, slow onset of therapeutic effect, numerous dietary and drug interactions, and a need for monitoring and dose adjustment. This not withstanding, warfarin remains the standard orally administered anticoagulant available. Patients on warfarin therapy require regular monitoring in part because of its narrow therapeutic index and interactions with food and other drugs. Injectable agents that are also widely used include low molecular weight heparins and the synthetic pentasaccharide fondaparinux. Thus, discovering and developing safe and efficacious oral anticoagulants for the prevention and treatment of a wider range of thrombotic diseases has become increasingly important.
A key strategy for the discovery and development of new anticoagulants has been the targeting of specific enzymes within the blood coagulation cascade. One approach is to inhibit thrombin and thrombin generation by targeting the inhibition of coagulation factor Xa. Preparations of beta-amino acid-, aspartic acid- and diaminopropionic-benzamides or preparations of heterocycles containing ethylenediamine moiety as activated blood coagulation factor Xa inhibitors were described in International Patent Applications WO 01/038309 and WO 2004/058728.
Factor Xa, a trypsin-like serine protease, is crucial to the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade that is responsible for fibrin clot formation. Animal models have suggested that inhibiting FXa and/or thrombin has the potential for providing excellent antithrombotic efficacy. Even more it has been suggested that dual inhibitors could result in an improved activity when compared to single point inhibition of the coagulation cascade.